A voltage-dependent sodium channel is a protein responsible for the initiation and propagation of action potentials in neurons. The voltage-dependent sodium channel is composed of one larger α subunit with four domains, each consisting of six transmembrane segments, as a common structure and two smaller β subunits. A major part of the channel function is played by α subunit. To date, more than 10 different α subunit subtypes have been known (Goldin A L, Annals of the New York Academy of Sciences 868:38-50, 1999). Each voltage-dependent sodium channel subtype shows distinct distributions in the central and peripheral nerve tissues. These subtypes regulate neural excitability and play an important role in regulating physiological functions in individual tissues. It is also suggested that they are deeply associated with various pathological conditions (Goldin A L, Annual Review of Physiology 63:871-894, 2001).
In recent years, it has become clear that voltage-dependent sodium channels are deeply involved in neural transmission of pain, and sodium channel blockers are expected to be excellent pain therapeutics, especially neuropathic pain therapeutics (Taylor C P, Current Pharmaceutical Design 2: 375-388, 1996).
Neuropathic pain means a pain that results from dysfunction in the central or peripheral neurons and refers to diabetic neuropathic pain, cancer pain, trigeminal neuralgia, phantom limb, post herpetic neuralgia, thalamic pain, etc. The clinical picture of neuropathic pain includes stabbing pain, burning pain, hyperalgesia, allodynia, etc.
In medical scenes, non-steroidal anti-inflammatory drugs, narcotic analgesics such as morphine, etc. are used for the purpose of relieving pain. Recently, antiarrhythmic drugs and anticonvulsants, which are sodium channel blockers, have come to be used as well, for the purpose of relieving pain.
The non-steroidal anti-inflammatory drugs are not completely satisfied in terms of analgesic actions and involve the problem of side effects such as gastrointestinal disturbance or renal disorder. The narcotic analgesics such as morphine are effective for nociceptive pain, but encounter serious side effects on the alimentary, respiratory or central nervous system. In addition, these drugs are generally less effective for neuropathic pain.
The antiarrhythmic drugs such as lidocaine or mexiletine and the anticonvulsants such as carbamazepine, which are sodium channel blockers, have come to be used to relieve pain. Mexiletine has been approved and is available as an anti-diabetic neuropathic pain drug. However, these sodium channel blockers involve problems that they have central side effects such as convulsions or drowsiness, or peripheral side effects such as bradycardia and hence, have difficulty to increase a dose to a sufficient level, resulting in failure to achieve satisfactory analgesic effects.
As above, analgesics that are useful for the treatment of neuropathic pain and are excellent in safety have not been found yet. Accordingly, sodium channel blockers having an excellent analgesic action especially on neuropathic pain with minimized side effects have been desired.
Lidocaine, mexiletine, carbamazepine, etc. mentioned above are reported but do not fall under nitrogen-containing heterocyclic derivatives having styryl group.
Derivatives having a 1-pyridylalkylpiperidine as a basic skeleton are disclosed and have a sodium channel inhibitory activity (Patent Literature 1). In this literature, compounds having 2-cyclohexylmethyloxy-6-fluorophenylethenyl on the piperidine ring as a substituent are disclosed.
Also, compounds containing a mono-substituted phenylethenyl having a halogen or cyclohexylmethyloxy at the 2- or 3-position of a 1-aromatic heterocyclic group-alkylpiperidine ring as a substituent are described (Patent Literature 2).
On the other hand, compounds, not as sodium inhibitors but as metabotropic glutamate receptor (mGluR) inhibitors and analgesics, which are one of therapeutics for various diseases, based on mGluR inhibitory effects are disclosed (Patent Literatures 3-4). Specifically, there are described 2-pyridine compounds having styryl group (Patent Literature 3), thiazole, oxazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1H-1,2,4-triazole, 2-oxo-1,3,4-oxathiazole, 2H-tetrazole, 2-pyridine, pyridinium, pirazine, indolinium, benzothiophene, benzothiazonium, quinoline or quinolium compounds having styryl group (Patent Literature 4), imidazole compounds having styryl group (Patent Literature 5), and imidazole, 1,2,4-triazole or 2H-tetrazole compounds having styryl group (Patent Literature 6), but these compounds are unsaturated heterocyclic compounds having styryl group.
Furthermore, piperidine compounds having benzyl or phenylmethylene based on NMDA/NR2B antagonizing effect are disclosed (Patent Literature 7).
On the other hand, nitrogen-containing heterocyclic derivatives having styryl group, which are formed by combining groups, are disclosed (Patent Literatures 8 and 9) and among these derivatives, only the compounds that phenyl group and a nitrogen-containing heterocyclic ring are combined via a —O-lower alkylene-(Patent Literature 3), a —S-lower alkylene- or a -lower alkylene-C(O)O— are specifically disclosed (Patent Literature 4) but nitrogen-containing heterocyclic derivatives are neither disclosed specifically nor even suggested. Moreover, these derivatives are used as calcium channel antagonists (Patent Literature 8) or for promotion of acetylcholine release (Patent Literature 9) but nothing is disclosed or even suggested on any sodium channel inhibitory activity or any analgesic action.    Patent Literature 1    European Patent Publication No. 1254904    Patent Literature 2    WO03/84948 Pamphlet    Patent Literature 3    WO99/02497 Pamphlet    Patent Literature 4    WO01/16121 Pamphlet    Patent Literature 5    WO02/46166 Pamphlet    Patent Literature 6    WO99/08678 Pamphlet    Patent Literature 7    WO01/32615 Pamphlet    Patent Literature 8    WO94/13291 Pamphlet    Patent Literature 9    WO97/19059 Pamphlet